Ajoene, an experimental anti-leukemic drug: mechanism of cell death

Dirsch, Verena M.; Antlsperger, Dorothee; Hentze, Hannes; Vollmar, Angelika M.

doi:10.1038/sj.leu.2402337

Cited by 73 publications

(47 citation statements)

References 40 publications

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“…Therefore, we examined whether activation of JNK is a consequence of MMP or occurs independently of mitochondrial perturbation. Previous data have shown that cells overexpressing mitochondria-protecting Bcl-x L exhibit a significant reduced cell death rate in response to ajoene (Dirsch et al, 2002). In contrast, ajoene-induced activation of JNK is not altered by Bcl-x L overexpression ( Figure 2a).…”

Section: Ajoene-induced Jnk Activation Occurs Independently Of Mitochmentioning

confidence: 64%

“…As mentioned before, ajoene induces the intrinsic pathway of apoptosis involving the induction of ROS upstream of mitochondria-dependent caspase activation (Dirsch et al, 2002). The aim of the present study was to clarify the participation of MAPKs and Akt in the apoptotic signaling of this organosulfur compound.…”

Section: Introductionmentioning

confidence: 74%

“…Ajoene has been shown to induce inner and outer MMP within 4 h (Dirsch et al, 2002), a time frame that seems to correlate with JNK activation (Figure 1a). Therefore, we examined whether activation of JNK is a consequence of MMP or occurs independently of mitochondrial perturbation.…”

Section: Ajoene-induced Jnk Activation Occurs Independently Of Mitochmentioning

confidence: 91%

“…Ajoene, an organosulfur compound originating from garlic (Agarwal, 1996), has been shown to induce dose (5-40 mm)-and time (5-24 h)-dependent apoptosis in promyeloleukemic cells via the intrinsic pathway of apoptosis involving mitochondrial membrane permeabilization (MMP), the release of cytochrome c, and subsequent caspase activation (Dirsch et al, 1998(Dirsch et al, , 2002. Additionally, ajoene was demonstrated to initiate the generation of reactive oxygen species (ROS) independent of mitochondrial perturbation and upstream of caspase activation (Dirsch et al, 1998(Dirsch et al, , 2002.…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, ajoene was demonstrated to initiate the generation of reactive oxygen species (ROS) independent of mitochondrial perturbation and upstream of caspase activation (Dirsch et al, 1998(Dirsch et al, , 2002. Ajoene-induced ROS production was shown to be linked to induction of apoptosis (Dirsch et al, 1998) raising the question as to what signaling events may lead from ROS generation to ajoene-mediated mitochondrial 'activation' and cell death.…”

Section: Introductionmentioning

confidence: 99%

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Ajoene-induced cell death in human promyeloleukemic cells does not require JNK but is amplified by the inhibition of ERK

et al. 2003

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Treatment of human promyeloleukemic HL-60 cells with the experimental antileukemic drug ajoene induces the activation of the mitogen-activated protein kinases (MAPKs) c-Jun NH 2 -terminal kinase (JNK), p38 and extracellular signal-regulated kinases (ERK) 1/2 as well as the survival kinase Akt. JNK activation occurred in HL-60/neo, HL-60/bcl-x L , and in HL-60 cells pretreated with the pan-caspase inhibitor zVAD-fmk, indicating that JNK activation is not dependent on ajoene-induced mitochondria perturbation and subsequent caspase activation. Cells overexpressing a dominant-negative JNK showed no altered sensitivity towards ajoene suggesting that the activation of JNK is not necessary for ajoeneinduced cell death. Inhibition of p38 MAPK by SB 203580 had no influence on ajoene-mediated apoptosis. In contrast, inhibition of ERK1/2 vastly enhanced ajoeneinduced cell death. The survival kinase Akt, in contrast, did not participate in ajoene-induced death signaling as shown by the use of the phosphatidylinositol-3-kinase inhibitor wortmannin. Thus in contrast to the previous findings regarding stress-induced cell death, ajoenemediated activation of JNK and p38 has no impact on ajoene-induced apoptosis in HL-60 cells. Blockade of ERK1/2 but not Akt pathways leads to sensitization of cells against ajoene-mediated apoptosis supporting the view that inhibition of ERK1/2 is a valuable strategy to increase the sensitivity of promyeloleukemic cells towards ajoene.

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Section: Ajoene-induced Jnk Activation Occurs Independently Of Mitochmentioning

confidence: 64%

Section: Introductionmentioning

confidence: 74%

Section: Ajoene-induced Jnk Activation Occurs Independently Of Mitochmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ajoene-induced cell death in human promyeloleukemic cells does not require JNK but is amplified by the inhibition of ERK

et al. 2003

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Apoptosis induction by sulfur‐containing compounds in malignant and nonmalignant human cells

Fimognari

Lenzi

Hrelia

2009

Environ and Mol Mutagen

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Plants have traditionally represented a main source for the discovery of many biologically active substances with therapeutic values. Sulfur-containing compounds exhibit pleiotropic biological effects supporting their potential use in multitargeted cancer prevention and treatment. As potential anti-cancer agents, they have been shown to inhibit or retard the growth of various cancer cells in culture and implanted tumors in vivo. The compounds significantly inhibit experimental tumorigenesis in a wide range of animal models. A critical and well-elucidated cellular mechanism involved in the anticancer activities of sulfur-containing compounds is the induction of apoptosis through the fine-tuning of orchestrated intracellular signal transduction. This review summarizes the established proapoptotic activities of sulfur-containing compounds in malignant and nonmalignant cells with a special focus on their molecular mechanisms. The potential toxicological implications of proapoptotic effects on normal cells will also be discussed.

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The garlic compound ajoene targets protein folding in the endoplasmic reticulum of cancer cells

Kaschula

Hunter

Cotton

et al. 2015

Molecular Carcinogenesis

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Ajoene is a natural allylsulfur compound found in crushed garlic that arrests growth and induces apoptosis in cancer cells. To gain mechanistic insights into the cytotoxicity of ajoene in cancer cells, two fluorescently labelled ajoene analogs with dansyl- (DP) and fluorescein- (FOX) tags were synthesized. The tagged ajoenes were found to retain their activity at inhibiting proliferation and inducing apoptosis in MDA-MB-231 human breast-cancer and WHCO1 human esophageal-cancer cells. Both tagged ajoenes localized to the endoplasmic reticulum (ER) in MDA-MB-231 cells as observed by live cell confocal laser scanning microscopy (CLSM) and confirmed by generating an MDA-MB-231 cell line expressing yellow fluorescent protein (YFP) in the ER. DP appears to S-thiolate multiple protein targets in MDA-MB-231 cells as observed by immunoblotting under non-reducing conditions only; and a competition assay demonstrated that DP and Z-ajoene in fact share the same target. Ajoene S-thiolation interfered with protein folding and led to an accumulation of misfolded protein aggregates and activated the unfolded protein response (UPR). Consistent with this mechanism, increased levels of GRP78 and total ubiquitinated proteins were observed; and an ER-folded protein, type-1 collagen, was tracked to the proteasome following ajoene treatment. The intracellular protein aggregates were observed by CLSM and transmission electron microscopy (TEM). This is the first time that ajoene has been shown to target protein folding in the ER of cancer cells. © 2015 Wiley Periodicals, Inc.

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Ajoene, an experimental anti-leukemic drug: mechanism of cell death

Cited by 73 publications

References 40 publications

Ajoene-induced cell death in human promyeloleukemic cells does not require JNK but is amplified by the inhibition of ERK

Ajoene-induced cell death in human promyeloleukemic cells does not require JNK but is amplified by the inhibition of ERK

Apoptosis induction by sulfur‐containing compounds in malignant and nonmalignant human cells

The garlic compound ajoene targets protein folding in the endoplasmic reticulum of cancer cells

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